United's Portuguese winger replaced South Korean wide man Park Ji-Sung in the 59th minute - a move which was to finally clinch maximum points from two games for the Red Devils.
Wayne Rooney found Ronaldo on the right and his 66th minute cross was headed across his own goal by Aston Villa central defender Olof Mellberg. Waiting to pounce at the far post was Ruud van Nistelrooy and he touched the ball over the line from close range for the only goal of the game.
Without several key players, Villa had made life hard for United, although they failed to manage a single shot on target in the game.
With new signing Kevin Phillips injured, Juan Pablo Angel was too often an isolated figure up front.
At the back, it was a different story where Villa, boosted by a five-man midfield, were solid.
Van Nistelrooy blasted a 30-yard free-kick narrowly wide in the 11th minute, but it was to be another 17 minutes before United again threatened the Villa goal.
United's main threat of the first half came from Park and, when he was set up by neat passing between Rooney, van Nistelrooy and Paul Scholes, the South Korean's fierce shot from the left side of the Villa box was brilliantly turned on to the bar and over by goalkeeper Thomas Sorensen.
Three minutes later, Villa were almost caught cold when Scholes lofted his corner to Rooney a yard from the Villa penalty area and his superb shot with the outside of his left boot was cleared off the line by Peter Whittingham.
After United's burst of pressure, Villa again tightened up, although Scholes almost broke the deadlock in first-half injury-time when his vicious 30-yard shot swerved inches wide of a post.
Two minutes after the break, Rooney set up van Nistelrooy, whose shot from the left corner of the box went narrowly wide of a post.
The busy Park was again near soon after, finishing a neat one-two with Rooney in the box, but seeing his shot skid across goal.
Ronaldo and Gabriel Heinze replaced Park and John O'Shea after 59 minutes and it was to prove the catalyst from another surge of United pressure.
In the 62nd minute, Ronaldo's cross from the right was met by van Nistelrooy, whose flying header was brilliantly saved by Sorensen.
Within seconds, the Danish goalkeeper was again Villa's saviour.
This time, Darren Fletcher provided the cross from the right and it was Ronaldo, craning his neck to meet the ball, whose header was magnificently tipped away by Sorensen.
Another fine move by United down the right in the 65th minute almost brought a goal.
Fletcher found Gary Neville racing away in acres of space and his cross was inches away from being turned in by van Nistelrooy at the far post.
But United had less than a minute to wait before the Dutchman scored his second goal of the Premiership campaign.
Villa had Sorensen to thank yet again in the 72nd minute when he produced another fine acrobatic save, this time to keep out a Scholes header from Neville's right-wing cross.
Villa boss David O'Leary brought on winger Nobby Solano, the subject of Liverpool interest with striker Milan Baros moving in the opposite direction, and he sparked some life into his side's wilting attack.
Villa's former United midfield man Eric Djemba-Djemba cleared van Nistelrooy's effort off his line with four minutes to go, but it did not matter as referee Phil Dowd ruled the Dutchman offside.
Man of the Match: Cristiano Ronaldo - Sparked his side into life by making the only goal of the game for Ruud Van Nistelrooy seven minutes after coming on as a substitute.